Using whole-cell electrophysiology in brain slices, we find that physiological effects of 5-HT1A and 5-HT2A receptor activation were dramatically reduced following withdrawal of either cocaine self-administration (CSA) or yoked cocaine administration (CYA) in pyramidal neurons. Moreover, these reduced effects of 5-HT at these receptors persisted for many weeks after cocaine withdrawal, suggesting they may be involved in long-term aspects of cocaine addiction, such as drug craving. As 5-HT in the OFC is implicated in behavioral flexibility, learning and other cognitive abilities, our experiments provide novel information as to the role that 5-HT plays in cocaine addiction, and in the impaired decision-making exhibited during cocaine addiction and withdrawal. In addition, since 5-HT is linked to several neuropsychiatric disorders, such as depression, anxiety, dementia, impulsive-aggression disorder (IAD), obsessive-compulsive disorder (OCD), and post-traumatic stres disorder (PTSD), these experiments provide valuable information as to the clinical utility of targeting the 5-HT system in the OFC as potential therapies. Our recent efforts in this project have focused on developing a transgenic rat model that will permit us to examine the role of 5-HT in the regulation of a class of important neurons in the OFC, known as fast-spiking (FS), parvalbumin (PV), interneurons. These neurons constitute a minority of the total cell population in the OFC, but are important because they use the inhibitory neurotransmitter, gamma-aminobutyric acid (GABA), to coordinate the activity of the much larger population of pyramidal neurons, via extensive synaptic connections. Therefore, these neurons are integral to the computational processes that are necessary for normal OFC function, and are likely to be involved in psychiatric and addiction disorders in which this brain are contributes. To study these neurons our transgenic core has developed a rat model in which the PV gene promoter drives the expression of cre recombinase. This permits selective expression fluorescent proteins and opsins, such as channelrhodopsin-2 (ChR2), that allows us to study these neurons, and manipulate their activity with light. Our current experiments have focused on the characterization of these PV cells in brain slices, and in defining the effects of 5-HT receptors in the regulation of their activity. We have also begun to determine whether CSA alters the basal function of these PV neurons, and whether CSA alters the effects of 5-HT on this class of cell. It is hoped that the identification of the roles of these neurons in psychiatric illness and addiction will aid in developing novel targeted therapeutic approaches for treatment in humans.